Curcumin
Curcumin is a component of turmeric, the yellow spice derived from roots of the plant Curcuma longa, and is also known as diferuloylmethane, or (E,E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dion. Curcumin has the structure:

There are several curcumin analogs that include the natural curcuminoids demethoxycurcumin and bisdemethoxycurcumin, and synthesized analogs such as curcumin derivatives. Curcumin derivatives retain the basic structural features of curcumin but include modifications such as acetylation, alkylation, glycosylation, and amino acetylation of the phenolic hydroxyl group, demethylation of the methoxy groups, or acetylation, alkylation and substitution of the reactive methylene group of the linker, among other modifications. Curcumin analogues are all other compounds with structural analogy to curcumin and include natural compounds such as ferulic acid, cinnamic acid, caffeic acid, capsaicin, and gingerol. Metal complexes of curcumin have been described as well. To increase the bioavailability of curcumin, various drug-delivery systems have been developed, ranging from polymeric and solid lipid nanoparticles to liposomal formulations, and microparticle and microemulsion formulations.
Curcumin has potent anti-cancer properties which are chemopreventive and chemotherapeutic. No discernible side effects have been reported in phase I and II clinical trials in the U.S. Studies in tumor cells and animal tumor models have shown that curcumin can inhibit proliferation in various cancers either alone or in combination with other chemotherapeutic agents. Due to its ability to cross the brain blood-barrier, an impediment to drug delivery of many chemotherapeutics to the brain, curcumin can inhibit medulloblastoma growth in a medulloblastoma in vivo model (Lee et al., 2011, BMC Cancer 11:144). Other cancers in which curcumin has been proposed to be effective include, but are not limited to, hematological cancers (acute lymphoblastic leukemia ALL, acute T cell leukemia ATL, acute myelogenous leukemia AML, promyelocytic leukemia, erythromyeloblastoid leukemia) and lymphomas (Burkitt's lymphoma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, follicular lymphoma, primary effusion lymphoma), multiple myeloma, gastrointestinal cancers (esophagus, intestine, liver, pancreas, colon, rectum), bladder, kidney, prostate, breast, cervix, ovary, lung melanoma, and brain tumors. Although curcumin has been identified as one of the major natural agents that inhibit tumor growth, it is not known why curcumin preferentially kills cancer cells. No reliable marker exists that could predict which tumors will respond to curcumin treatment.
Curcumin can arrest cell-cycle progression and induce apoptosis in various cancer cells (Sa and Das, 2008, Cell Division 3:14). Curcumin induces G2/M arrest and apoptosis in medulloblastoma cells (Bangaru et al., 2010, Anticancer Research 30:499-504; Elamin et al., 2010, Molecular Carcinogenesis 49:302-314; Lee et al., 2011, BMC Cancer 11:144). However, the molecular mechanism how curcumin induces cell cycle arrest at G2/M remains elusive.
Curcumin affects a multitude of molecular targets including transcription factors, receptors, kinases, inflammatory cytokines, and other enzymes (for a comprehensive review see Aggarwal et al, 2007, Advances in Experimental Medicine and Biology, 595, 1-75). Curcumin modulates multiple signaling pathways including pathways involved in cell proliferation (cyclin D1, c-myc), cell survival (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), and apoptosis (caspase-8, 3, 9). Other pathways affected by curcumin include those comprising protein kinases (JNK, Akt, AMPK), tumor suppressors (p53, p21), death receptors (DR4, DR5), mitochondrial pathways and endoplasmic reticulum stress responses. Curcumin has also been shown to alter the expression and function of COX2 and 5-LOX at the transcriptional and post-translational levels. Thus, it is possible, that many of the cellular and molecular effects observed in curcumin treated cells might be due to downstream effects rather than direct interactions with curcumin.
Although there are now a multitude of studies on curcumin's cellular effects, surprisingly little is known about the direct interactions of curcumin with its target molecules. One of the better characterized interactions is the binding of curcumin to the cystic fibrosis transmembrane conductance regulator (CFTR) (Bernard et al., 2009, The Journal of Biological Chemistry, 284: 30754-30765). Curcumin can crosslink CFTR polypeptides into SDS-resistant oligomers in microsomes and in intact cells. However, the ability of curcumin to rapidly and persistently stimulate CFTR channels was unrelated to the crosslinking activity.
After leukemias, brain cancers are the second most common cancers in children. In general, the prognosis for patients diagnosed with brain tumors is worse than for many other pediatric cancers and as a group account for more than a quarter of childhood deaths from cancer. Medulloblastoma, the most common brain cancer in children, is incurable in about a third of patients and survivors suffer from serious therapy-related side effects. These include cognitive and intellectual deficits in IQ, memory, attention, language and mathematical ability, hearing loss, impaired growth and bone development, endocrinological problems, and the development of secondary cancers.
Safe and effective treatment options for medulloblastoma and other cancers, and the ability to predict the response to such a treatment, is critical to patient management.
Cdc27/APC3
Spindle Assembly Checkpoint (SAC) is required to block sister chromatid separation until all chromosomes are properly attached to the mitotic apparatus. The SAC prevents cells entering anaphase by inhibiting the ubiquitination of cyclin B1 and securin by the Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase. The target of the SAC is the essential APC/C activator, Cdc20.
APC/C is partially activated through phosphorylation of core subunits. One core subunit, the protein Cdc27 (also known as APC3) undergoes mitosis-specific phosphorylation which seems to enhance the affinity between APC/C and p55Cdc20, thereby ensuring its activation (King et al., 1995, Cell, 81: 279-288; Kraft et al., 2003, EMBO Journal, 22 2/1: 6598-6609; Yu et al., 2007, Molecular Cell, 27: 3-16; Kimata et al., 2008, Molecular Cell 32: 576-583). Analysis of mitosis-specific phosphorylation sites in Cdc27 has revealed that most of them are clustered in confined regions, mainly outside of the tetratrico-peptide repeats (TPR) (Kraft et al., 2003, EMBO Journal, 24: 6598-6609).
Human Cdc27 was described by Tugendreich et al., 1993, Proc. Natl. Acad Sci USA 90: 10031-10035). The amino acid sequence of Cdc27 is provided under GenBank Accession No. NP—001107563.1. The nucleotide sequence of the encoding m RNA is provided under GenBank Accession No. NM—001114091.1. Both sequences are incorporated herein by reference.